Thiazolyl benzoic acid compounds

ABSTRACT

m-(thiazol-4-yl) benzoic acids substitued in 2- and optionally 5-position of the thiazol ring by lower alkyl, phenyl-alkyl, phenyl, halo-phenyl, lower alkylphenyl or lower alkoxy-phenyl, and on the phenyl ring of the benzoic acid moiety by halogen, hydroxyl, lower alkyl or lower alkoxy. These compounds possess fibrinolytic, platelet stickiness decreasing and antiulcer properties and have an impact on the immunological processes.

v [22] Filed:

United States Patent [191 Malen et al.

[ THIAZOLYL BENZOIC ACID COMPOUNDS [75] Inventors: Charles Malen,Fresnes; Pierre Desnoyers, Fontenay-aux-Roses, both of France [73]Assignee: Science Union et Cie Societe Francaise De Recherche Medicale,Suresnes, France Dec. 2, 1969 21 App]. No.: 881,590

[30] Foreign Application Priority Data Dec. I6, 1968 Great Britain59720/68 I [52] U.S. Cl. 260/302 R, 424/270 [51] Int. Cl C07d 91/32 [58]Field of Search 260/302 R [56] References Cited UNITED STATES PATENTS3.558,64l l/l97 l Sarett et al 260/302 R 1111' 3,821,237 June 28, 19 743,676,451 7/1972 Sarett et al 260/302 R Primary ExaminerR. J. GallagherAttorney, Agent, or FirmGor.don W. Hueschen 5'7 ABSTRACT' 14 Claims, N0Drawings THIAZOLYL BENZOIC ACID COMPOUNDS The present invention providesthiazolyl benzoic acid compounds of the general formula (I):

COOH Elect ll, wherein:

R and R are selected from the group consisting of: a linear or branchedloweralkyl chain containing 1 to 5 carbon atoms inclusive, a phenylalkylradical, and a phenyl radical optionally substituted by one or morehalogen atoms, lower alkyl or lower alkoxy radicals containing 1 to 5carbon atoms inclusive and for R, a hydrogen atom, and

A is selected from the group consisting of: a hydrogen atom, a halogenatom, a hydroxy radical and a lower alkyl or lower alkoxy radicalcontaining 1 to 5 carbon atoms inclusive.

These compounds are new and may beprepared by a known method describedby Hantzsch et al. Ann 294 l (1888), by reacting an a-haloketone of thegeneral formula (11):

wherein R, and A have the meanings defined above and X represents achlorine or bromine atom, with a thioamide of the general formula (III):

s Biz-(1 NEI z. 2

EXAMPLE 1 2-hydroxy-5-(2-methyl thiazol-4-yl) benzoic acid COOH Asolution of 53 g (0.2 mol) of Z-hydroxy-S-(abromoacetyl) benzoic acid'in250 ml of slightly warm ethanol was dropped, for 15 minutes, in asolution of 15 g (0.2 mol) of thioacetamide in 60 ml of ethanol, whilestirring vigorously. The reaction was slightly exothermic, and a whiteproduct gradually precipitated. Stirring was maintained for one hour,then the reaction mixture was diluted with 500 ml of water. Theprecipitate was filtered off, washed with water and the product wasrecrystallized from ethanol. 406 g of 2-hydroxy 5- (2-methylthiazol-4-yl) benzoic acid, M.P. (K.B.) 250-253C, were obtained (yield83 percent). A second yield of product was obtained by concentration ofthe ethanolic mother liquors. 3.1 g (0.0425 mol) of diethylamine wasadded to a suspension of 10 g (0.0425 mol) of the acid prepared above in50 ml of ethanol. The mixture was stirred for 30 minutes thenconcentrated to dryness. The residue was recrystallized from benzene.10.3 g of diethylammonium 2-hydroxy-5-(2- methyl thiazol-4-yl) benzoateare obtained, M.P. (M.l(.) 128132C with progressive recrystallizationand second M.P. 249250C (yield 78 percent).

Over its melting point, the diethylammonium salt gives diethylamineregenerating then the corresponding acid; the second melting pointcorresponds to the complete transformation in free acid.

EXAMPLES 2 14 The following compounds were prepared according to themethod described in Example 1:

2. 2-hydroxy-5-(2-phenyl thiazol-4-yl) benzoic acid, M.P. (M.K.)210-211C with sublimation (acetonitrile), starting from2-hydroxy-5-(a-bromoacetyl) benzoic acid and thiobenzamide.

3. 2-hydroxy-5-[2-(3,4-dimethoxyphenyl) thiazol- 4-yl] benzoic acidmonohydrate, M.P. (K.B.) 140C then 218222C (ethanol), starting from2-hydroxy-5- (at-bromoacetyl) benzoic acid and thioveratramide.

4. 2-methoxy-5-(2-phenyl thiazol-4-yl) benzoic acid, M.P. (K.B.)169-170C, starting from 2-methoxy-5- (oz-bromoacetyl) benzoic acid andthiobenzamide.

5. Diethylammonium 2-methoxy-5-(2-methyl thiazol-4-yl) benzoate,instantaneous M.P. (K.B.) 130-132C (benzene), M.P. (K.B.) of thecorresponding acid l57l60C, starting from 2-methoxy-5-(achloroacetyl)benzoic acid and thioacetamide.

6. Diethylammonium 3-(2-methyl thiazol-4-yl) benzoate, M.P. (K.B.) 137C,M.P. (K.B.) of the corresponding acid 194-196C, starting from3-(abromoacetyl) benzoic acid and thioacetamide.

7. Diethylammonium 2-chloro-5-(2-m'ethyl thiaz0l-.

4-yl) benzoate, M.P. (M.K.) -l50C (benzene), M.P. (M.K.) of thecorresponding acid 206209C, starting from 2-chloro-5-(tit-bromoacetyl)benzoic acid and thioacetamide.

8. 3-(2,5-dimethyl thiazol-4-yl) benzoic acid, M.P. (M.K.) l50l54C(acetonitrile) starting from 3-(abromopropionyl) benzoic acid andthioacetamide.

9. 2-methoxy-5-(2-benzyl thiazol-4-yl) benzoic acid, M.P. (M.K.)136139C, starting from 2-methoxy-5- (a -bromoacetyl) benzoic acid andphenylethane thioamide.

10. Diethylammonium 2-methyl-3-(2-isobutyl thiazol-4-yl) benzoate,starting from 2-methyl-3-(abromoacetyl) benzoic acid andthioisovaleramide.

l l. Diethylammonium -2-bromo-5-(2-ethy1-5-phenyl thiazol-4-yl)benzoate, starting from 2-bromo-5- (phenyl a-bromoacetyl) benzoic acidand thiopropionamide.

l2. Diethylammonium 3-(2-methyl-5-paratolyl thiazol-4-yl)-4-ethoxybenzoate, starting from 3- (paratolyl a-bromoacetyl)-4-ethoxy benzoicacid and thiofonnamide.

13. 3-ethyl-5-(Z-methyl-S-propyl thiazol-4-yl) benzoic acid, startingfrom 3-ethyl-5-(a-bromovaleryl) benzoic acid and thioacetamide.

l4. 3-(2-parachlorophenyl thiazol-4-yl) benzoic acid, starting from3-(a-bromoacetyl) benzoic acid and parachlorothiobenzamide. The newcompounds of thiazolyl benzoic acid and their physiologicallytolerablesalts of the present invention possess valuable pharmacological andtherapeutic properties, especially with regard to fibrinolysis, plateletstickiness, ulcer and immunological processes.

Their toxicity is very weak and the LD in mice varies from l87,5 mg/kgto 1000 mg/kg by intraperitoneal administration and from 1000 mg/kg to2000 mg/kg by the oral route.

The fibrinolytic activity was studied by the method described by vonKaulla in Thromb. Diath. Haemorrhag. 5, 489-494 (1961). By administeringintravenously to the rat 5 to mg/kg of the new products, a, decrease of6 to 64 percent of the euglobulin lysis time may be observed 10 to 30minutes after the injection. By oral administration, 50 to l00 mg/kgprovoked a decrease of 4 to 54 percent of the euglobulin lysis time,after 1 to 3 hours.

Using the method of S. Wessler (J. Clin. Invest. 34, 647-65] (1955)), itcan be observed that the compounds ofthe invention, at a dose of 50mg/kg l.V., inhibit totally or partially the formation of thrombus inthe vena jugularis of the rabbit, provoked by injection of aheterologous human or rat serum, showing thus an activity of theproducts on fibrinolysis and immunological conditions. It is to be notedthat in this assay human or rat serum induces a thrombus in 96 per centof test rabbits.

The activity on the platelet stickiness was evidenced by the method ofE. W. Salzman (J. Lab. Clin. Med. 62, 724 (1923)). It was found that thenew compounds administered to the rabbit at 10 to mg/kg l.V. and at 50to 100 mg/kg P.O. decrease the platelet stickiness by to 50 percent.

The new products have no notable effect on other blood clotting factorsat the active dose on fibrinolysis and so do not'provoke haemorrhage;they are effective by the oral route and so distinguish themselves fromknown enzymatic fibrinolytic substances, as streptokinase. urokinase andplasmin. To our knowledge, no other synthetic chemical substance hasthis advantageous and safe activity and no similar product is at thepresent time on the pharmaceutical market. The mode of action seems tobe the stimulation of the plasminogen proactivator, since the compoundshave no effect on bovin plasma, which is devoid of proactivator.

The new products also inhibit in the rat the development of the ulcer ofrestraint (Method of S. Bonfils et al. Rev. Fr. Et. Clin. Biol. Xl. 343(1966)). At the dose of 2 to 200 mg/kg l.P., 25 to 75 percent of theanimals are protected from ulceration, which occurs in 92 percent of thecontrol animals.

An inhibition of the gastric secretion by the new products can also beobserved by the method of H. Shay et al. (Gastroenterology 5, 43(1945)). Doses of .10 to 150 mg/kg intraperitoneally decrease thehydroucts in therapy, especially in the prevention and the treatment ofthrombosis, thromboembolic diseases, infarctus, arteriosclerosis,gastric ulcer and hypersecrelllOn.

The present invention also provides pharmaceutical compositionscontaining a compound of the general formula (I) or a physiologicallytolerable salt thereof, in admixture or conjunction with a suitablepharmaceutical carrier, such, for example, as distilled water, glucose,lactose, talc, starch. stearate of magnesium and cocoa butter. Thesepharmaceutical compositions may be in form of tablets, dragees,capsules, suppositories or solutions, in order to be administered by theoral, rectal or parenteral route, at doses of 5 to 500 mg l to 5 times aday.

The following Example illustrates such a pharmaceutical preparation:

for 1 tablet to be drageified.

Using an effective amount of the new compounds, a human or animal beingmay successfully be prevented from thromboembolic disorders, myocardialor other organs infarctus and arteriosclerosis. The treatment may safelybe continued over a long period of months or even years by the oralroute, without notable side effects, such as haemorrhagic tendency,which is always the danger of the. anticoagulants acting on otherclotting factors.

Another advantage of the invention is the relatively low price of thecompounds compared to the very expensive enzymatic substances, such asstreptokinase.

We claim:

1. A compound selected from the group consisting of:

A. 2 hydroxy-5-(2-phenyl thiazol-4-yl) benzoic acid,2-methoxy5-(2-methyl thiazol-4-yl) benzoic acid, 2-chloro-5-(2-methylthiazol-4-yl) benzoic acid, 3-(2,5-dimethyl thiazol-4-yl) benzoic acid,2- hydroxy-5-[2-(3,4-dimethoxyphenyl) thiazol-4-yl] benzoic acid,2-methoxy-5-(2-phenyl thiazol-4-yl) benzoic acid, 3-(2-methylthiazol-4-yl) benzoic acid, 2-methoxy-5-(2-benzyl thiazol-4-yl) benzoicacid, 2-methyl-3-(2-isobutyl thiazol-4-yl) benzoic acid,2-bromo-5-(2-ethyl-5-phenyl thiazol-4-yl) benzoic acid,3-(2-methyl-5-paratolyl thiazol-4-yl)- 4-ethoxy benzoic acid,3-ethyl-5-(2-methyl-5- propyl thiazol-4-yl) benzoic acid, 3-(2-parachlorophenyl thiazol-4-yl) benzoic acid, and

B. physiologically acceptable addition salts with mineral or organicbases.

2. A compound of claim 1 which is 2-hydroxy-5-(2- phenyl thiazol-4-yl)benzoic acid.

3. A compound of claim 1 which is 2-methoxy -5-(2- methyl thiazol-4-yl)benzoic acid 4. A compound of claim 1 which is 2-chloro-5-(2- methylthiazol-4 yl) benzoic acid.

5. A compound of claim 1 which is 3-(2,5-dimethyl thiazol-4-yl) benzoicacid.

benzyl thiaz'ol-4-yl) benzoic acid.

10. A compound of claim l which is diethylammonium2-methyl-3-(2-isobutyl thia2ol-4-yl) benzoate.

6 11. A compound of claim 1 which is diethylammonium 2-bromo-5-(2-et hyl-5-phe nyl thiazol-4-yl) benzoate.

12. A compound of claim 1 which is diethylammonium3-(2-methyL5-paratolyl thiazol-4-yl)-4-ethoxy benzoate.

13. A compound of claim 1 which is 3-ethyl-5-( 2-methyl-5 -p ropylthiazol-4-yl) benzoic acid.

14. A compound of claim 1 which is 3-(2- parachlorophenyl thiazol-4-yl)benzoic acid.

2. A compound of claim 1 which is 2-hydroxy-5-(2-phenyl thiazol-4-yl)benzoic acid.
 3. A compound of claim 1 which is 2-methoxy-5-(2-methylthiazol-4-yl) benzoic acid
 4. A compound of claim 1 which is2-chloro-5-(2-methyl thiazol-4-yl) benzoic acid.
 5. A compound of claim1 which is 3-(2,5-dimethyl thiazol-4-yl) benzoic acid.
 6. A compound ofclaim 1 which is 2-hydroxy-5-(2-(3,4-dimethoxy-phenyl) thiazol-4-yl)benzoic acid monohydrate.
 7. A compound of claim 1 which is2-methoxy-5-(2-phenyl thiazol-4-yl) benzoic acid.
 8. A compound of claim1 which is diethylammonium 3-(2-methyl thiazol-4-yl) benzoate.
 9. Acompound of claim 1 which is 2-methoxy-5-(2-benzyl thiazol-4-yl) benzoicacid.
 10. A compound of claim 1 which is diethylammonium2-methyl-3-(2-isobutyl thiazol-4-yl) benzoate.
 11. A compound of claim 1which is diethylammonium 2-bromo-5-(2-ethyl -5-phenyl thiazol-4-yl)benzoate.
 12. A compound of claim 1 which is diethylammonium3-(2-methyl-5-paratolyl thiazol-4-yl)-4-ethoxy benzoate.
 13. A compoundof claim 1 which is 3-ethyl-5-(2-methyl-5-propyl thiazol-4-yl) benzoicacid.
 14. A compound of claim 1 which is 3-(2-parachlorophenylthiazol-4-yl) benzoic acid.